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Background: Although exercise stress electrocardiography (ECG) is a
popular tool for detecting coronary artery disease (CAD), the induced
ST-depression without coronary artery stenosis (FST) remains a challenge for
accurate diagnosis. Exercise-induced ST depression is related to poor prognosis
even in non-obstructive disease; however, its determinants have not been fully
defined. We sought to investigate whether ventriculo-vascular interactional
indexes such as arterial stiffness index, exercise hemodynamic parameters and
echocardiographic left ventricular (LV) functional parameters were related to
FST. Methods: In the current study, 609 participants who underwent both
supine bicycle exercise echocardiography and brachial-ankle pulse wave velocity
(baPWV) measurement without exercise-induced regional wall motion abnormalities
(RWMA) were analyzed. Referral reasons for stress test were CAD detection or
evaluation of patency of previous revascularization. Stepwise graded supine
bicycle exercise was performed with simultaneous ECG recording and
echocardiography after full conventional resting echocardiography. The FST was
defined as newly developed
Although exercise stress electrocardiography (ECG) is widely used and recommended for initial diagnostic test to detect coronary artery disease (CAD), false-positive ST depression (FST) remains a challenge for precise diagnosis [1, 2, 3]. Despite the relatively high false positive rate of exercise ECG for diagnosing obstructive CAD, exercise ECG paradoxically has strong prognostic value for future cardiovascular events and all-cause mortality, even in asymptomatic individuals or patients with low pre-test probability of CAD [4, 5, 6]. Therefore, we need to reveal the potential mechanism of FST during exercise. In addition, the prevalence of FST and the exact determinants of FST in supine bicycle exercise in patients with risk factors of CAD or previous history of revascularization, have not been fully understood [7, 8, 9]. Previous studies suggested that women, microvascular dysfunction and combined left ventricular hypertrophy, coronary milking phenomenon were potentially related to FST [2, 9, 10]. However, they did not accurately prove the physiological mechanism by basic experimental studies [10]. In addition, we easily meet the cases with FST without above situations.
Cardiac afterload is a major determinant of myocardial ischemic threshold [11]. There is a stiffness gradient from distensible elastic proximal arteries to muscular distal arteries in normal conditions [11, 12]. However, in a stiff arterial tree, the speed of propagation of the arterial pulse through the aorta is increased, and the increased speed of the forward traveling wave (pulse wave velocity) implies an earlier reflection of backward traveling wave from the periphery [11, 12]. Therefore, systolic blood pressure increases and diastolic pressure for coronary perfusion decreases in stiff aorta. However, relationship between arterial stiffness or exercise induced afterload index and FST has not been previously investigated.
Therefore, in this study we aimed to evaluate actual prevalence and potential associates to FST in patients with risk factors of CAD or previous history of revascularization using supine bicycle exercise stress echocardiography. In addition, we sought to investigate whether ventriculo-vascular interactional indexes such as arterial stiffness index, exercise hemodynamic parameters and echocardiographic left ventricular (LV) functional parameters were related to FST in cases without baseline ST depression, hypertrophic cardiomyopathy or dynamic LV outflow tract obstructions.
We retrospectively analyzed the results of supine bicycle exercise
echocardiography from April 2006 to December 2013 at a single tertiary referral
hospital. Referrals for an exercise echocardiography sought to detect CAD or to
evaluate the patency of previous revascularization. Patients with concomitant
cardiomyopathy, dynamic left ventricular (LV) outflow tract obstruction, valvular
heart disease, or pulmonary artery disease were excluded. In addition, patients
with baseline ST depression and exercise-induced regional wall motion
abnormalities (RWMA) were also excluded. Finally, 768 patients were included in
the study, of which 609 brachial-ankle pulse wave velocity (baPWV) measurements
were performed within 1 month of exercise echocardiography (Fig. 1). Primary end
points comprised horizontal or downsloping ST segment depression of
Schematic illustration of study flow. HCM, hypertrophic cardiomyopathy; LVOTO, left ventricular outflow tract obstruction; VHD, valvular heart disease; PH, pulmonary hypertension; CAD, coronary artery disease; FST, false ST-depression.
Before conventional echocardiography, blood pressure (BP) was measured on
sitting position using an oscillometric blood pressure monitoring device
(TM-2665P, AND, CA, USA). With echo-Doppler evaluation, LV mass index, relative
wall thickness, LV ejection fraction, left atrial volume index (LAVI), mitral
inflow pulse wave Doppler, and systolic and diastolic tissue velocities at the
septal mitral annulus were measured. Pulmonary arterial systolic pressure (PASP)
was calculated as 4
BaPWV were simultaneously measured using a vascular testing device (VP-2000;
Colin Medical Technology, Komaki, Japan). After participants had rested in the
supine position for
Resting echocardiography images were obtained in the standard parasternal and
apical views. Symptom limited multistage supine bicycle exercise testing was
performed with a variable load bicycle ergometer (Model AE2, Medical Positioning, Inc.,
Kansas City, MO, USA). Patients pedalled at a constant speed starting at a
workload of 25 watts (W), with the workload increasing by 25 W every 3 minutes
according to ramp protocol. If patients could persist exercise, we did not stop
the exercise. In cases who could not reach the 85% maximal heart rate, we did
not apply the IV atropine. During exercise test, 12-lead ECG was simultaneously
monitored. At each stage of exercise and recovery phase, 12-lead ECGs were
printed out and recorded according to study protocol. Echocardiography was
performed using a GE Vivid 7 ultrasound system (GE Medical systems, Horten, Norway) with a 2.5-MHz
transducer during rest, exercise, and recovery. Patients who were taking beta
blockers, we recommended to quit them from 3 days before exercise test.
Pre-exercise baseline BP was measured in the supine position immediately before
the exercise test. During exercise, the BP was measured at the end of each stage
on the left arm using an oscillometric BP monitoring device (Tango, Tango+, SunTech
medical, Morrisville, NC, USA). BP was measured after 1 minute, 3 minutes, and 5
minutes during recovery while stress images were acquired. At each stage of
exercise and recovery, basal, mid-, and apical LV short axis views, along with
apical 4-, 3-, and 2-chamber views, were obtained. Hypertensive response was
defined as systolic BP
The normality of distribution of continuous variables was assessed by
Shapiro-Wilk test. Descriptions of continuous variables were presented as the
mean
The median age of the study participants was 65 (59.0–70.5) years (64 in men
vs. 66 in women, p
Total | With FST | Without FST | p value | ||
---|---|---|---|---|---|
(n = 609) | (n = 103) | (n = 506) | |||
Age, years | 65 (59–71) | 67 (61–73) | 64 (58–70) | 0.003 | |
Males, n (%) | 387 (66) | 63 (61) | 324 (64) | 0.582 | |
BSA, m |
1.73 |
1.70 |
1.73 |
0.072 | |
Body mass index, kg/m |
24.4 (23.0–16.5) | 24.1 (22.8–26.5) | 24.6 (23.0–26.5) | 0.640 | |
Hypertension, n (%) | 466 (77) | 79 (77) | 387 (77) | 0.962 | |
Diabetes, n (%) | 169 (28) | 23 (22) | 146 (29) | 0.178 | |
History of revascularization, n (%) | 121 (20) | 18 (18) | 103 (20) | 0.504 | |
Resting SBP, mmHg | 119 (107–132) | 118 (107–132) | 119 (107–132) | 0.680 | |
Resting DBP, mmHg | 74 |
72 |
74 |
0.061 | |
Resting HR, bpm | 67 (67–75) | 67 (61–71) | 68 (61–75) | 0.204 | |
Resting PP, mmHg | 45 (36–54) | 47 (37–56) | 44 (35–53) | 0.046 | |
Medication | |||||
ARB or ACEi user, n (%) | 540 (89) | 93 (90) | 447 (88) | 0.569 | |
BB user, n (%) | 173 (28) | 35 (34) | 138 (27) | 0.169 | |
CCB user, n (%) | 501 (82) | 83 (81) | 418 (83) | 0.624 | |
Nitrate or its analogues user, n (%) | 140 (23) | 31 (30) | 109 (22) | 0.072 | |
baPWV, cm/s | 1497 (1346–1721) | 1571 (1394–1848) | 1485 (1341–1690) | 0.012 | |
ABI | 1.13 (1.08–1.18) | 1.14 (1.09–1.20) | 1.13 (1.07–1.18) | 0.032 |
FST, false-positive ST-depression; BSA, body surface area; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; PP, pulse pressure; ARB, angiotensin receptor antagonist; ACEi, angiotensin converting enzyme inhibitor; BB, beta blocker; CCB, calcium channel blocker; baPWV, brachial-ankle pulse wave velocity; ABI, ankle brachial index.
Total | With FST | Without FST | p value | |
---|---|---|---|---|
(n = 609) | (n = 103) | (n = 506) | ||
Peak SBP, mmHg | 185 (168–202) | 191 (168–203) | 185 (167–201) | 0.337 |
Peak DBP, mmHg | 88 (81–97) | 87 (80–97) | 89 (82–97) | 0.229 |
Peak HR, mmHg | 133 (122–142) | 136 (125–144) | 133 (121–142) | 0.149 |
Exercise time, sec | 720 (540–900) | 720 (540–900) | 720 (540–900) | 0.329 |
(747.8 |
(730.5 |
(751.3 |
(0.383) | |
Exercise capacity, watt | 100 (75–125) | 100 (75–125) | 100 (75–125) | 0.329 |
(103.9 |
(101.5 |
(104.3 |
(0.383) | |
Peak workload, mmHg × bpm/1000 | 24.1 |
24.9 |
23.9 |
0.024 |
Hypertensive response, n (%) | 145 (24) | 33 (32) | 112 (22) | 0.031 |
LVESP, mmHg | 104.6 |
104.4 |
104.6 |
0.884 |
SVR, dynes-sec-cm |
1.50 (1.25–1.74) | 1.44 (1.24–1.69) | 1.51 (1.25–1.74) | 0.321 |
SV, mL | 67.6 (57.8–78.0) | 68.4 (60.6–79.8) | 67.2 (57.0–77.1) | 0.228 |
Ea, mmHg/mL | 1.55 (1.31–1.83) | 1.51 (1.28–1.77) | 1.56 (1.32–1.85) | 0.247 |
Ed | 0.15 (0.12–0.20) | 0.16 (0.12–0.20) | 0.15 (0.12 –0.19) | 0.178 |
TAC, mL/mmHg | 1.54 (1.21 –1.89) | 1.48 (1.18–1.85) | 1.55 (1.21–1.90) | 0.287 |
LVEDD, mm | 45 (43–48) | 45 (42–48) | 45 (43–48) | 0.766 |
LVESD, mm | 30 (27–32) | 30 (27–32) | 30 (27–32) | 0.986 |
RWT | 0.42 (0.38 –0.46) | 0.43 (0.38–0.47) | 0.42 (0.38–0.46) | 0.117 |
LVMI, g/m |
84 (74–97) | 84 (74–96) | 89 (78–101) | 0.057 |
LAVI, mL/m |
23.8 (20.0 –27.6) | 25.0 (21.4–29.6) | 23.4 (19.5–37.2) | 0.005 |
LVEF, % | 66 (62–70) | 66 (61–71) | 66 (62–70) | 0.828 |
e’, cm/sec | 6.0 (5.0–7.0) | 6.0 (5.0–7.0) | 6.0 (5.0–7.0) | 0.628 |
a’, cm/sec | 9.1 (8.0–11.0) | 9.0 (8.0–10.0) | 9.8 (8.0 –11.0) | 0.255 |
s’, cm/sec | 8.0 (7.0–9.0) | 7.0 (7.0–9.0) | 8.0 (7.0–9.0) | 0.471 |
E/e’ | 10.3 (8.4–12.8) | 10.6 (9.1–13.2) | 10.2 (8.3–12.8) | 0.043 |
PASP, mmHg | 25 (22–28) | 27 (23–30) | 25 (22–28) | 0.001 |
*mean
Univariate analysis | Multivariate analysis | |||
---|---|---|---|---|
OR (95% CI) | p value | OR (95% CI) | p value | |
Age, per year | 1.04 (1.01–1.06) | 0.008 | 1.02 (0.99–1.06) | 0.160 |
Male | 1.13 (0.73–1.75) | 0.582 | ||
Hypertension | 1.01 (0.61–1.67) | 0.962 | ||
Diabetes | 0.71 (0.43–1.17) | 0.179 | ||
ACEi/ARB use | 1.23 (0.61–2.49) | 0.570 | ||
Calcium channel blocker use | 0.87 (0.51–1.50) | 0.624 | ||
Beta-blockage use | 1.37 (0.87–2.16) | 0.170 | ||
Nitrate use | 1.57 (0.98–2.51) | 0.061 | ||
Systolic BP-resting, per mmHg | 1.002 (0.99–1.01) | 0.691 | ||
Diastolic BP-resting, per mmHg | 0.98 (0.962–1.001) | 0.062 | ||
Mean arterial pressure, per mmHg | 0.99 (0.973–1.009) | 0.338 | ||
Pulse pressure, per bpm | 1.01 (0.999–1.028) | 0.062 | ||
Resting heart rate, per bpm | 0.98 (0.961–1.003) | 0.090 | ||
LV mass index, per g/m |
1.01 (0.997–1.020) | 0.129 | ||
Relative wall thickness | 6.92 (0.31–155) | 0.222 | ||
Exercise duration, per sec | 1.000 (0.999–1.001) | 0.383 | ||
LVEF, per % | 0.995 (0.968–1.024) | 0.748 | ||
s’, per cm/s | 0.97 (0.86–1.08) | 0.559 | ||
e’, per cm/s | 0.97 (0.86–1.09) | 0.609 | ||
E/e’ | 1.05 (0.998–1.107) | 0.059 | ||
LA volume index, per mL/m |
1.03 (1.002–1.054) | 0.037 | 1.02 (0.99–1.05) | 0.225 |
PASP at rest, per mmHg | 1.07 (1.02–1.11) | 0.003 | 1.06 (1.02–1.11) | 0.007 |
Peak heart rate, per bpm | 1.014 (1.001–1.027) | 0.039 | 1.02 (1.01–1.03) | 0.007 |
Peak systolic BP, per mmHg | 1.003 (0.993–1.013) | 0.529 | ||
Peak diastolic BP, per mmHg | 0.99 (0.97–1.01) | 0.231 | ||
Hypertensive response at peak | 1.66 (1.04–2.64) | 0.033 | 0.96 (0.53–1.74) | 0.881 |
Peak workload (rate-pressure product), per (mmHg × bpm)/1000 | 1.05 (1.01–1.10) | 0.024 | ||
baPWV, per m/s | 2.40 (1.30–4.44) | 0.005 | 2.75 (1.40–5.41) | 0.003 |
ABI | 16.33 (1.30–205.84) | 0.031 |
ARB, angiotensin receptor antagonist; ACEi, angiotensin converting enzyme inhibitor; BP, blood pressure; LV, left ventricular; LA, left atrial; LVEF, LV ejection fraction; e’, peak early diastolic mitral annular velocity; s’, peak systolic mitral annular velocity; E/e’, the ratio of mitral peak velocity of early filling to e’; PASP, pulmonary arterial systolic pressure; baPWV, brachial-ankle pulse wave velocity; ABI, ankle brachial index.
Several previous studies showed that increased arterial stiffness is linked to endothelial dysfunction [17] in patients with CAD risk factors [18, 19, 20]. Although the aortic and peripheral arterial stiffness do not directly affect cardiac electrophysiology, they could affect LV diastolic function during aerobic exercise through ventricular-vascular interaction [21, 22]. In this study, although we did not measure the chamber diastolic function throughout the exercise test, increased baPWV could potentially affect electrical stability at peak exercise, which could then result in ST depression without definite RWMA. In addition, a previous study showed that arterial stiffness indexes, such as carotid-femoral PWV and carotid augmentation index were associated with reduced ischemic threshold in patients with moderate CAD [12]. Increased PWV shifts pressure wave reflections from diastole to systole reduce diastolic perfusion pressure [11]. Therefore, a stiff aorta has a diminished capacity to serve as a blood reservoir during cardiac ejection, such that blood is available for coronary perfusion during diastole [12].
The prevalence of FST was high in our study, which was consistent with previous studies [2, 9]. This might be due to the heterogeneous patient inclusion, which involved patients with a history of previous coronary revascularization, and supine bicycle exercise rather than upright exercise. The incidence of FST was also different according to exercise protocol. In the recent studies done by upright cycle ergometer exercise, the incidence of FST was 22% [2, 9] and 18.8% in treadmill exercise test [9]. The ST change could be a result of coronary microcirculatory dysfunction without radial contractile abnormality [2]. According to our study results, higher PWV, hypertensive response, and higher heart rate at peak exercise were independently correlated with FST. Relationship between higher PWV and FST reflects that resting afterload affects endocardial function through impaired vascular-ventricular interaction. In addition, relationship between hypertensive response to exercise and FST also reflects that exercise-induced increased afterload affects endocardial function through impaired vascular-ventricular interaction [22]. Some previous studies showed that hypertensive response was linked to FST without CAD [10, 23]. According to our study results, hypertensive response due to increased arterial stiffness [2, 24, 25, 26] is associated with FST, but hypertensive responses at a younger age can be linked to augmentation of SV due to vigorous LV contraction [24]. Therefore, in older adults with increased arterial stiffness, we need to take care of possibility of FST. In our study diastolic dysfunctional parameters, such as higher left atrial volume index and tricuspid regurgitant velocity, were linked to FST, indicating that ST depression without radial RWMA might not be a true “normal perfusion condition”, but rather an occult or a subclinical impaired perfusion status. This might support the poor prognosis of exercise-induced ST depression reported in several previous studies. When the ST segment downsloping is secondary to microvascular disease, the inducible subendocardial ischemia cannot achieve the critical mass to generate segmental wall motion anomalies of the LV. It was also reported that endothelial dysfunction could modify the repolarization process through the prolongation of repolarization phase at the subendocardial level [27]. Higher peak heart rate was related to FST possibly due to change in atrial repolarization according to previous study [28]. Contrary to some previous studies presenting higher incidence of FST in women [29, 30], the incidence of FST did not significantly differ between sexes in our study, despite higher trends in women. However, our study results were consistent with a recent large study performed in 3000 consecutive patients [9]. The study also showed an equal prevalence of FST in men and women, and concluded that FST in men could be predicted before the test with clinical characteristics such as left ventricular hypertrophy in ECG, known CAD and hypertension etc., while most cases in women could not [9]. A unique finding in our study was that baPWV also tends to be related to FST in women, which suggests that increased arterial stiffness may be a potential cause of FST in women. According to our study, higher heart rate and hypertensive response at peak exercise were linked to FST. This indicates that beta-blockers for heart rate reduction, nitrate for improvement in microcirculation, or antihypertensive medication can improve FST by reducing rate-pressure product. Some patients with exercise intolerance or those not trained for exercise may experience rapid heart rate elevation even during low intensity exercise [31, 32]. Therefore, graded and regular cardiopulmonary exercise training could be beneficial to prevent rapid heart rate elevation during exercise. Receptor for advanced glycation end-product antagonist, which potentially destiffen large arteries, may have favourable effects in preventing ST depression during exercise [33]. Nevertheless, further research is required.
This study had several limitations. First, the patients included in the study were heterogeneous, from presenting symptoms of atypical chest pain to having a history of previous coronary revascularization. Therefore, small coronary vessel diseases or microcirculatory dysfunctional patients could be included. Second, although exercise-induced RWMA was thoroughly interpreted by both sonographers and cardiologists who were experts in echocardiography, by reviewing three short axis views and 4-, 3-, and 2 chamber views, the possibilities of missed RWMA, especially in the right coronary artery or left circumferential artery territory, still existed. However, as we reviewed the results one more time in patients with FST to detect missed RWMA, the possibility of missed RWMA was low. Third, in order to elucidate the potential mechanisms of ST change and its relationship with increased arterial stiffness at peak exercise, LV longitudinal systolic and diastolic function need to be evaluated. Fourth, as higher peak heart rate was linked to FST in our study, delta ST depression/delta heart rate, which has been shown to have higher sensitivity for CAD in a previous study [34], should be applied in future studies. Fifth, as we did not use intravenous atropine to achieve target heart rate due to symptom limited exercise test, some patients did not reach targeted maximal heart rate.
FST is not rare, especially in supine bicycle exercise. In cases with increased arterial stiffness, higher PASP and peak heart rate were related to exercise-induced ST depression. Therefore, stress-induced RWMA should be evaluated to detect epicardial coronary artery stenosis in patients with exercise-induced ST depression in ECG. Although not related to radial contraction abnormality, exercise induced ST depression without CAD might be associated with subclinical myocardial ischemia through arterial stiffness and subendocardial diastolic dysfunction.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
HC and EYC designed study. JS, ISK, JYK, PKM, YWY, SJR, BKL, BKH and HMK contributed to the data collection, interpretation, and analysis. HC and EYC contributed to drafting the manuscript. All authors contributed to the manuscript. All authors read and approved the final manuscript.
All study protocols were approved by the institutional review board of our hospital (2016-0378-001), and the need for informed consents was waived due to the retrospective nature of the study.
Not applicable.
This research is supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0481, HC20C0082).
The authors declare no conflict of interest.
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